Whole body periodic acceleration in normal and reduced mucociliary clearance of conscious sheep

Autoři: Juan R. Sabater aff001;  Marvin A. Sackner aff001;  Jose A. Adams aff003;  William M. Abraham aff001
Působiště autorů: Department of Research, Mount Sinai Medical Center, Miami Beach, Florida, United States of America aff001;  Department of Medicine, Mount Sinai Medical Center, Miami Beach, Florida, United States of America aff002;  Division of Neonatology, Mount Sinai Medical Center, Miami Beach, Florida, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224764


The purpose of this investigation was to ascertain whether nitric oxide (NO) released into the circulation by a noninvasive technology called whole body periodic acceleration (WBPA) could increase mucociliary clearance (MCC). It was based on observations by others that nitric oxide donor drugs increase ciliary beat frequency of nasal epithelium without increasing mucociliary clearance. Tracheal mucous velocity (TMV), a reflection of MCC, was measured in sheep after 1-hour treatment of WBPA and repeated after pretreatment with the NO synthase inhibitor, L-NAME to demonstrated action of NO. Aerosolized human neutrophil elastase (HNE) was administered to sheep to suppress TMV as might occur in cystic fibrosis and other inflammatory lung diseases. WBPA increased TMV to a peak of 136% of baseline 1h after intervention, an effect blocked by L-NAME. HNE reduced TMV to 55% of baseline but slowing was reversed by WBPA, protection lost in the presence of L-NAME. NO released into the circulation from eNOS by WBPA can acutely access airway epithelium for improving MCC slowed in cystic fibrosis and other inflammatory lung diseases as a means of enhancing host defense against pathogens.

Klíčová slova:

Acceleration – Cystic fibrosis – Epithelium – Mucus – Neutrophils – Nitric oxide – Sheep – Tobacco mosaic virus


1. Messina MS, O’Riordan TG, Smaldone GC. Changes in mucociliary clearance during acute exacerbations of asthma. The American review of respiratory disease. 1991;143(5 Pt 1):993–7. doi: 10.1164/ajrccm/143.5_Pt_1.993 2024856.

2. O’Riordan TG, Zwang J, Smaldone GC. Mucociliary clearance in adult asthma. The American review of respiratory disease. 1992;146(3):598–603. doi: 10.1164/ajrccm/146.3.598 1519834.

3. Smaldone GC, Foster WM, O’Riordan TG, Messina MS, Perry RJ, Langenback EG. Regional impairment of mucociliary clearance in chronic obstructive pulmonary disease. Chest. 1993;103(5):1390–6. doi: 10.1378/chest.103.5.1390 8486016.

4. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. The New England journal of medicine. 2006;354(3):241–50. doi: 10.1056/NEJMoa043891 16421365.

5. Sabater JR, Lee TA, Abraham WM. Comparative effects of salmeterol, albuterol, and ipratropium on normal and impaired mucociliary function in sheep. Chest. 2005;128(5):3743–9. doi: 10.1378/chest.128.5.3743 16304342.

6. Scott DW, Walker MP, Sesma J, Wu B, Stuhlmiller TJ, Sabater JR, et al. SPX-101 Is a Novel Epithelial Sodium Channel-targeted Therapeutic for Cystic Fibrosis That Restores Mucus Transport. Am J Respir Crit Care Med. 2017;196(6):734–44. doi: 10.1164/rccm.201612-2445OC 28481660.

7. Sabater JR, Mao YM, Shaffer C, James MK, O’Riordan TG, Abraham WM. Aerosolization of P2Y(2)-receptor agonists enhances mucociliary clearance in sheep. J Appl Physiol (1985). 1999;87(6):2191–6. doi: 10.1152/jappl.1999.87.6.2191 10601167.

8. Hirsh AJ, Sabater JR, Zamurs A, Smith RT, Paradiso AM, Hopkins S, et al. Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease. The Journal of pharmacology and experimental therapeutics. 2004;311(3):929–38. doi: 10.1124/jpet.104.071886 15273255.

9. Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med. 2007;58:157–70. doi: 10.1146/annurev.med.58.071905.105316 17217330.

10. Fischer BM, Voynow JA. Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species. Am J Respir Cell Mol Biol. 2002;26(4):447–52. doi: 10.1165/ajrcmb.26.4.4473 11919081.

11. Amitani R, Wilson R, Rutman A, Read R, Ward C, Burnett D, et al. Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium. Am J Respir Cell Mol Biol. 1991;4(1):26–32. doi: 10.1165/ajrcmb/4.1.26 1898852.

12. Caldwell RA, Boucher RC, Stutts MJ. Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport. Am J Physiol Lung Cell Mol Physiol. 2005;288(5):L813–9. doi: 10.1152/ajplung.00435.2004 15640288.

13. O’Riordan TG, Otero R, Mao Y, Lauredo I, Abraham WM. Elastase contributes to antigen-induced mucociliary dysfunction in ovine airways. Am J Respir Crit Care Med. 1997;155(5):1522–8. doi: 10.1164/ajrccm.155.5.9154852 9154852.

14. Wright CD, Havill AM, Middleton SC, Kashem MA, Lee PA, Dripps DJ, et al. Secretory leukocyte protease inhibitor prevents allergen-induced pulmonary responses in animal models of asthma. The Journal of pharmacology and experimental therapeutics. 1999;289(2):1007–14. 10215681.

15. Chowienczyk PJ, Kelly RP, MacCallum H, Millasseau SC, Andersson TL, Gosling RG, et al. Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus. Journal of the American College of Cardiology. 1999;34(7):2007–14. doi: 10.1016/s0735-1097(99)00441-6 10588217.

16. Adams JA, Bassuk J, Wu D, Grana M, Kurlansky P, Sackner MA. Periodic acceleration: effects on vasoactive, fibrinolytic, and coagulation factors. J Appl Physiol (1985). 2005;98(3):1083–90. doi: 10.1152/japplphysiol.00662.2004 15501928.

17. Adams JA, Moore JE Jr., Moreno MR, Coelho J, Bassuk J, Wu D. Effects of periodic body acceleration on the in vivo vasoactive response to N-omega-nitro-L-arginine and the in vitro nitric oxide production. AnnBiomedEng. 2003;31(11):1337–46. 213.

18. Sackner MA, Gummels E, Adams JA. Nitric oxide is released into circulation with whole-body, periodic acceleration. Chest. 2005;127(1):30–9. doi: 10.1378/chest.127.1.30 15653959.

19. Abraham WM, Ahmed A, Serebriakov I, Lauredo IT, Bassuk J, Adams JA, et al. Whole-body periodic acceleration modifies experimental asthma in sheep. Am J Respir Crit Care Med. 2006;174(7):743–52. doi: 10.1164/rccm.200601-048OC 16858016.

20. Li D, Shirakami G, Zhan X, Johns RA. Regulation of ciliary beat frequency by the nitric oxide-cyclic guanosine monophosphate signaling pathway in rat airway epithelial cells. Am J Respir Cell Mol Biol. 2000;23(2):175–81. doi: 10.1165/ajrcmb.23.2.4022 10919983.

21. Wyatt TA. Cyclic GMP and Cilia Motility. Cells. 2015;4(3):315–30. doi: 10.3390/cells4030315 26264028

22. Sackner MA, Hirsch J, Epstein S. Effect of cuffed endotracheal tubes on tracheal mucous velocity. Chest. 1975;68(6):774–7. doi: 10.1378/chest.68.6.774 1192854.

23. O’Riordan TG, Mao Y, Otero R, Lopez J, Sabater JR, Abraham WM. Budesonide affects allergic mucociliary dysfunction. J Appl Physiol (1985). 1998;85(3):1086–91. doi: 10.1152/jappl.1998.85.3.1086 9729587.

24. Sackner MA, Epstein S, Wanner A. Effect of beta-adrenergic agonists aerosolized by freon propellant on tracheal mucous velocity and cardiac output. Chest. 1976;69(5):593–8. doi: 10.1378/chest.69.5.593 5251

25. Howlin RP, Cathie K, Hall-Stoodley L, Cornelius V, Duignan C, Allan RN, et al. Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis. Molecular therapy: the journal of the American Society of Gene Therapy. 2017;25(9):2104–16. doi: 10.1016/j.ymthe.2017.06.021 28750737

26. Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O, et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free radical biology & medicine. 2003;35(7):790–6. doi: 10.1016/s0891-5849(03)00406-4 14583343.

27. Sackner MA, Patel S, Adams JA. Changes of blood pressure following initiation of physical inactivity and after external addition of pulses to circulation. Eur J Appl Physiol. 2019;119(1):201–11. doi: 10.1007/s00421-018-4016-7 30350153

Článek vyšel v časopise


2019 Číslo 11